GSK3 beta Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury
| Autor: | Vainio, Laura, Taponen, Saija, Kinnunen, Sini M., Halmetoja, Eveliina, Szabo, Zoltan, Alakoski, Tarja, Ulvila, Johanna, Junttila, Juhani, Lakkisto, Päivi, Magga, Johanna, Kerkelä, Risto |
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| Přispěvatelé: | Regenerative pharmacology group, Division of Pharmacology and Pharmacotherapy, Drug Research Program, HUSLAB, Department of Clinical Chemistry and Hematology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
cardiomyocyte hypertrophy
animal structures cardiomyocyte hypoxia ACTIVATED PROTEIN-KINASE INHIBITION S6 macromolecular substances CARDIOPROTECTION cell death glycogen synthase kinase 3 beta GLYCOGEN-SYNTHASE KINASE-3-BETA HEART GROWTH 1182 Biochemistry cell and molecular biology INACTIVATION GSK-3-BETA CARDIAC-HYPERTROPHY |
| Popis: | Prior studies show that glycogen synthase kinase 3 beta (GSK3 beta) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3 beta is constitutionally active and phosphorylation of GSK3 beta at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3 beta is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3 beta S389 phosphorylation in diseased hearts and utilized overexpression of GSK3 beta carrying ser & RARR;ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3 beta in primary cardiomyocytes. We found that phosphorylation of GSK3 beta at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3 beta S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia-reoxygenation. Overexpression of double GSK3 beta mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3 beta S389A or GSK3 beta S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3 beta S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3 beta at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy. |
| Databáze: | OpenAIRE |
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